Quaternary salts of bis-n, n-(4-benzyhydrylidene-1-alkyl-piperidine)-alkanes



United States Mam 3,036,080 QUATERNARY SALTS .OF BIS-N,N-(4-,BENZYHY-DRYLIDENE- l-ALKYL-PIPEINE-ALKANES Richard H. Barry, Bloomfield, N.J.,assignor to Scheriug gorporation, Bloomfield, N.J., a corporation of Newersey N Drawing. Filed July 5, 1960, Ser. No. 40,534 Claims. (Cl.260293) This invention relates to a new group of compounds havingdesirable pharmacological and physiological properties. Moreparticularly, this invention relates to a novel seriesof bisquaternaryderivatives of 4-benzhydrylidenel-lower alkyl piperidine which displayantibacterial ac tivity and pharmacological properties.

Thebis-quaternary compounds of this invention may be represented by thefollovw'ng general formula:

ll ll QZ-Q R R 2X wherein R is a lower alkyl radical, Z is a straight orbranched chain saturated hydrocarbon bridge having from 2 to 18 carbonatoms and X is the anion of a non-toxic acid such as chloride, iodide,bromide, phosphate, sulfate, nitrate, acetate or methosulfate.

Typical of the lower alkyl groups represented by R are alkyl groupscontaining from 1-4 carbon atoms; the methyl group being preferred. Anystraight or branched chain saturated hydrocarbon containing from 218carbon atoms may be employed as the hydrocarbon bridge (Z). Particularlypreferred are the straight chain hydrocarbons containing from 10-14carbon atoms.

The novel bis-quaternary compounds of this invention are prepared byreacting two molecular proportions of the tertiary base,4-benzhydrylidene-l-lower alkyl piperidine as described in United StatesPatent No. 2,739,968 which was issued on March 27, 1956, with onemolecular proportion of an alpha-omegaedihaloalkane as illustrated bythe following equation wherein R and Z are as defined above:

2 \O Hal-Z-Hal C \C The reaction is carried out usually in the absenceof a solvent and preferably at elevated temperatures (i.e. 75- 250 C.).The product is isolated by cooling the reaction mixture andrecrystallizing the solid product from suitable solvents such asmethanol, ethanol, acetone, etc. or from mixtures of these and/or otherconventional solvents. The resulting crude bis-quaternary halide maythen be purified byfurther recrystallization from solvents such asmentioned above.

The bis-quaternary halide, as prepared above, may be converted intoother bis-quaternary salts such as the phos- "ice vphate, sulfate,nitrate, acetate or methosulfate by conventional methodssuch as bydouble decompositions with an appropriate metal salt (e.g. silvernitrate, silver acetate, etc.) or by conversion of the bisquaternaryhalide to the corresponding hydroxide by treatment withmoist silveroxide followed by reaction with an acidhaving the desired radical (e.g.methylsulfuric acid).

The compounds of this invention have a wide spectrum of activity againstboth bacteria and fungi,,.particularly the gram positive cocci and thepathogenic dermatophytes. In addition, the compounds in this series showanti-cholinergic and anti-inflammatory activity. Compounds of thisseries are useful in pharmaceutical products, such as creams, ointments,and lotions for dermatological use; aqueous solutions and tinctures fordisinfecting and general antisepsis, for mouth washes, toothpastes,nasal drops and prophylactics; as preservatives for eye drops andparentei ally administered solutions and suspensions. Moreover, topicalpreparations containing the compounds of this invention are useful asbody deodorants and antiperspirants. The compounds may be combinedadvantageously for topical use with other adjunctive antifungal,keratolytic, anesthetic or anti-inflammatory compounds-thus makinguseful therapeutic admixtures thereby. Examples of utilitariandosageforms are given below, it being understood that 1,10-bis-N,N(4-benzhydrylidene-l-methylpiperidine)-decane dibromide isemployed in the following compositions for purposes of illustrationmerely and that any of the compounds of this invention could besubstituted therefor as a matter of choice.

Mouthwash: Parts by weight 1, l0-bis-N,N-(4-benzhydrylidene-1-methylpiperidine)decane dibromide 0.1 to 0.5vDisodium phosphate 0.25 Ethanol 25.0 Sorbitol solution 20.0 Cinnamonoil .05 Peppermint oil 0.1

Distilled water to 100.0.

Water-soluble antibacterial cream:

1,10-bis-N,N-(4 benzhydrylidene-l-methylpiperidine)decane dibromide 0.1to 1.0 Polyethylene glycol 400, 70% polyethylene glycol 4000, 30 ToAntibacterial cream:

1,10 bis N,N-(4-benzhydrylidene-l-meth- Mineral oil 0.0025 Sucrose tomake 1.0 gm.

Ointment:

1,10 =bis N,N-(4-benzhydrylidene-1-rnethylpiperidine)decane dibromide0.2 Carbitol 5.0 Oleyl alcohol 25.0 Glyceryl monostearate 10.0Microcrystalline wax 15.0 Petrolatum -n 30.0

Liquidipetrolatum to 1 00.0.

3 Topical paint:v Parts by weight 1,10 bis N,N-(4-benzhydrylidene-l-methylpiperidine)decane dibromide 1.0 Benzylalcohol 7 5.0 Distilled water 10.0 Propylene glycol to 100.0.

Dusting powder:

1,10 bis N,N-(4-benzhydrylidene-1-methylpiperidine)decane di'bromide 0.2Kaolin 50.0 Talc to 100.0.

' The following examples are further illustrative of the invention. Itis to be noted that although the examples are concerned with thepreparation of the bis-quaternary halides,all of these compounds may bereadily converted to other bis-quaternary salts by the conventionalmethods described above. No limitation is intended, therefore, except asdefined by the appended claims.

EXAMPLE 1 1,5-Bis-N,N-(4-Bezizhydrylidene-1-Methylpiperidine)- PentaneDibromide A mixture of 13.2 grams ofN-methyl-4-benzhydrylidenepiperidine and 5.8 grams of 1,5-dibromopentanewas heated together at 100 to 150 for 1-2 hours. The hygroscopiccompound when recrystallized from ethanolether mixture melted at 122 to124.

EXAMPLE 2 '1,6-Bis-N,N- (4-Benzhydrylidene-1-Methylpiperidine) HexaneDibromide A mixture of 13.2 grams ofN-methyl-4-benzhydrylidenepiperidine and 6.1 grams of 1,6-di'bromohexanewas heated at 80 to 85 whereupon an exothermic reaction occurred withthe temperature rising to 130. On coola ing, the mixture solidified.After several recrystallizations from methanol-ether, the compoundmelted at 283 to 284.8".

EXAMPLE 3 1,8-Bis-N,N-(4-Bervzhydrylidene-1-Metkylpiperidine) OctaneDibromide V A mixture of 13.2 grams ofN-methyl-4-benzhydrylidenepiperidine and 7.0 grams of 1,8-dibromo-octane was heated slowly to 170 for minutes. After cooling, theproduct was recrystallized from ethanol-ether, melting point 242 to 244.

EXAMPLE '4 1,9-Bis-N,N- (4-Benzhydrylidene-1-Methylpiperidine) NonaneDibromide Prepared in the same manner as in Example 3, 13.0 I

' grams of N-methyl-4-ben'zhydrylidenepiperidine and 7.5

grams of 1,9-di-bromononane gave a solid product which whenrecrystallized from ethanol ether melted at 235.4

7 EXAMPLE 5 1,10-Bis-N,N-(4-Benzhydlylidene-1-Methylpiperidine) DecqzneDibromide A solution of 131.5 grams of4-benzhydrylidene-lmethylpiperidine and 75 grams of 1,10-dibromodecanein 550 ml. of n butanol was stirred and refluxed for 6 hours. Thematerial which had solidified on cooling was filtered off and washedwith 1 liter of acetone. The product was stirred and refluxed with 1liter of acetone for 30 minutes, filtered off and dried at 65 in'avacuum oven. The compound melted at 227.0? to 229.8.

EXAMPLE 6 I 1,12-Bis-N,N- (4-Bcnzhydrylidene-I-Methylpiperidine)-Dodecane Dibromide According to the procedure of Example 3, 13.2 grams 4of N-methyl-4-benzhydrylidenepiperidine and 8.2 grams of1,2-dibromododecane were reacted to give the title product.

EXAMPLE 7 1,14-Bis-N,N-(4-Benzhydrylidene-I-Methylpiperia'ine)-Tetradecane Dibromide A mixture of 13.2 grams of N-methyl-4-benzhydry1-idenepiperidine and 8.9 grams of l,4-di'bromotetradecane were treatedaccording to Example 3 to yield the title product.

EXAMPLE 8 1,16-Bis-N,N-(4-Benzhydrylidene-I-Methylpiperidine) Hexaaecane Diiodide Following the procedure outlined in Example 3, themixture of 6.5 grams of N-methy1-4-benzhydrylidenepiperidine and 6.0grams of 1,16-diiodohexadecane yielded a product, when recrystallizedfrom ethanol ether, softens at 175, melts completely at 204.

EXAMPLE 9 1,5-Bis-N,N- (4-Benzhydrylidene-1-Methylpiperidine)3-Methylpentane Dibromide A mixture of 6.1 grams of3-methy1-1,S-dibromopentane and 13.2 grams of4-benzhydrylidene-l-methylpiperidine was heated ina metal bath at 100 to166 at which time the material became viscous. The viscous oil wasdissolved in ethanol and ethyl ether was added until no more oilseparated. The separated oil was ground with ether and the fine powderwhich resulted was filtered off. It melted at 86 to 92.

EXAMPLE 10 The dichloride and diiodide salts corresponding to thedibromide salts prepared according to Examples 1-7 and 9 and thedichloride and dibromide salts corresponding to the diiodide saltprepared according to Example 8 are obtained by substituting onemolecular proportion of an appropriate dihaloalkane for that specifiedin the above procedures; all other reaction conditions being the same.In this manner,

' l, 12- bis-N,N-( 4-benzhydrylidenel-methylpiperidine) -dodecanediiodide,1,14-bis-N,N-(4-benzhydrylidene-1-methylpiperidine)-tetradecanedichloride, j 1, l4-bis-N,N- 4-benzhydrylidenel-methylpiperidine)-tetradecane diiodide, 116-bis-N,N-(4-benzhydrylidene-1-methylpiperidine) hexadecane dibromide,1 ,16-bis-N,N-(4-benzhydrylidene-l-methylpiperidine) hexadecanedichloride,

5 1,5-bis-N,N-(4-benzhydrylidene-l-methylpiperidine)-3- methylpentanedichloride, and 1,5-bis-N,N-(4-benzhydrylidene-l-methylpiperidine) -3-methylpentane diiodide are readily prepared.

Where lower alkyl substituents other than methyl are desired (e.g.ethyl, propyl, butyl, etc.), it is merely necessary to substitute twomolecular proportions of an appropriately substituted4-benzhydrylidene-l-lower alkyl piperidine as the starting material inthe above examples.

I claim: 1. Compounds of the formula:

wherein R is a lower alkyl radical; Z is a member selected 25 from thegroup consisting of straight and branched chain saturated hydrocarbonshaving from 2 to 18 carbon atoms; and X is the anion of apharmaceutically acceptable non-toxic acid.

2. The compound 1,10-bis-N,N-(4-benzhydrylidene-1- methylpiperidine)-decane dibromide.

3. The compound 1,10-bis-N,N-(4-benzhydrylidene-1-metl1ylpiperidine)-de'cane dichloride.

4. The compound 1,10-bis-N,N-(4-benzhydrylidene-lmethylpiperidine)-decane diiodide.

5. The compound1,12-bis-N,N-(4-benzhydrylidene-lmethylpiperidine)-dodecane dibromide.

6. The compound 1,l2-bis-N,N-(4-benzhydrylidene-1- methylpiperidine)-dodecane dichloride.

7. The compound l,12-bisN,N-(4-benzhydrylidene-1-methylpiperidine)-dodecane diiodide.

8. The compound 1,14-bis-N,N-(4-benzhydrylidene-1- methylpiperidine)tetradecane dibromide.

9. The compound 1,14-bis-N,N-(4-benzhydrylidene-1- methylpiperidine)-tetradecane dichloride.

10. The compound 1,14-bis-N,N-(4-benzhydrylidene-1- methylpiperidine)-tetradecane diiodide.

No references cited.

1. COMPOUNDS OF THE FORMULA: